Substituted sulfonylacetamido cephalosporins

ABSTRACT

Cephalosporin compounds having various substituted sulfonylacetamido groups at position 7 have been prepared and have antibacterial activity.

United States Patent De Marinis et al.

SUBSTITUTED SULFONYLACETAMIDO CEPHALOSPORINS Inventors: Robert M. DeMarinis, King of Prussia; John R. E. Hoover, Glenside, both of Pa.

Assignee: SmithKline Corporation,

Philadelphia, Pa.

Filed: Dec. 3, 1974 Appl. No.: 529,163

Related us. Application Data Division of Ser. No. 249,858, May 3, 1972,Pat. No. 3,865,819.

US. CL... 260/243 C; 260/326.42; 260/515 M; 260/518 R; 260/526 S;260/534 S Int. Cl. ...C07D 501/22; C07D 501/24; C07D 50l/28; A6lK 31/545field of Search 260/243 C Dec. 23, 1975 [56] References Cited UNITEDSTATES PATENTS 3,382,238 5/l968 Dolfini 260/239.l

Primary Examiner-Richard J. Gallagher Assistant Examiner-Diana G. RiversAttorney, Agent, or Firm-Stuart R. Suter; Alan D. Lourie; William H.Edgerton 7] ABSTRACT Cephalosporm compounds having various substitutedsulfonylacetamido groups at position 7 have been prepared and haveantibacterial activity.

8 Claims, No Drawings SUBSTITUTED SULFONYLACETAMIDO CEPHALOSPORINS Thisis a division of application Ser. No. 249,858 filed May 3, 1972 now US.Pat. No. 3,865,819.

This invention relates to cephalosporin compounds which haveantibacterial activity, in particular, compounds having a substitutedsulfonylacetamido substituent at position 7 of the cephem nucleus.

The compounds of this invention are represented by the followingstructure.

Preferred compounds are those where A is CH S-Het and in particularwhere Het is tetrazolyl, 1,3,4- thiadiazolyl, 1,3,4-xadiazolyl,1,2,4-triazolyl, 1,2,3- triazolyl and the substituted derivativesthereof. Also preferred are compounds where X is methyl, ethyl, propyl,trifluoromethyl, phenyl, amino and dimethylamino.

The compounds of this invention are prepared by acylation of a7-aminocephalosporanic acid with the appropriately. substitutedsulfonylacetic acid. The carboxyl group is activated prior or duringthe'acylation reaction by one of the methods well known in the art.

. These include the mixed anhydride, acid halide and activated estermethods and the use of a coupling rea- 0 xcn coua S 3 gent such asd1cyclohexylcarbod11m1de.

N A The alkyl and arylsulfonylacetic acids are prepared 00 by oxidationof the appropriate substituted mercaptoacetic acid with an oxidizingagent; for example, methylmercaptoacetic acid is oxidized withm-chloroperbenzoic acid to give methylsulfonylacetic acid. Alter- Whefeinatively and substituted mercaptoacetic acid can be X is lower alkyl ofC -C phenyl, unsubstituted or converted to an activated ester, suchasthe N-hydroxsubstituted with nitro, amino, dialkylamino, each alkylysuccinimide ester or the 2,4-dinitrophenyl ester, and having C -Chydroxy, alkoxy (C -C or halogen; then oxidized to the activatedsulfonylacetateAmino- CF NH or mono or dialkylamino, each alkyl of Csulfonylacetic acids .(i.e., XSO CH COOl-l where X is C A is hydrogen,methyl, acetoxymethyl, pyridiniumamino or dialkylamino) are preparedfrom commermethyl, CH S-Het, CH SR, or CH OR; cially availablechlorosulfonylacetyl chloride by known Het is a 5 or 6-memberedheterocyclic ring containmethods (J. Amer. Chem. Soc., 81, 5655 (1959);Briting one to four atoms selected from the group consistish Pat. No.1,067,965). ing of N, O and S, unsubstituted or substituted with The7-aminocephalosporins where A is Cl-l s-l-let are from one to two groupsselected from lower alkyl, cyprepared by known methods fromlaminocephalospocloalkyl or alkenyl, each having one to four carbonranic acid (7-ACA) and the appropriate heterocyclic atoms; lower alkoxyor alkoxyalkyl, each alkoxy or mercaptan compound. The compounds where Ais alkyl having one to four carbon atoms; hydroxy; CF pyridiniummethylare prepared by acylation of 7-ACA NHR; NR SR; or halogen; and thenreaction with pyridine by known procedures. R is hydrogen or lower alkyl(C -C and The compounds where A is hydrogen, methyl, alkylthi- M ishydrogen, alkali metal cation, nontoxic ammoomethyl, or alkoxymethyl areprepared from materials nium cation, or when A is pyridiniummethyl anknown in the art, readily prepared by known methods anionic charge. ordescribed herein. Cephalosporins with a wide variety of acyl groups atThe compounds of this invention have broad-specsition 7 are known in theprior art including substitrum antibacterial activity with minimuminhibitory tuted sulfinylalkanoyl groups. The present inventionconcentrations (MIC) ranging from 0.1 to 200 ug/ml. relates tosubstituted sulfonylacetamidocephalospo- Table 1 shows MlCs for avariety of compounds within rins, having a doubled oxidized sulfur atom.the scope of this invention against various Gram-positive andGram-negative bacteria.

TABLE 1 Compd. a b c d e f g h i j k l m n O NO. MlC (pg/ml) 54293 3.11.6 0.4 200 12.5 25 12.5 125 200 12.5 25 200 200 55848 1.6 1.6 0.2 12.525 3.1 6.3 200 3.1 12.5 200 200 57286 3.1 l.6 0.2 3.1 12.5 1.6 3.1 2003.1 3.1 200 200 200 57359 1.6 0.8 V 0.2 50 50 100 12.5 6.3 200 12.5 25200 200 200 57360 0.8 0.4 0.1 25 25 100 25 12.5 200 25 25 200 200 20059345 0.8 0.8 25 0.1 100 100 100 50 100 200 '50 so 200 200 200 59393 1.61.6 25 0.1 50 50 50 25 25 200 12.5 25 I 200 200 100 59454 25 25 200 10.4 200 200 200 200 200 200 200 200 200 200 200 59586 1.6 0.8 100 0.2100 6.3 25 3.1 3.1 200 1.6 v 12.5 200 200 200 59623 0.8 0.8 100 0.1 10025 50 6.3 6.3 200 3.1 25 200 200 59641 0.4 0.4 100 0.1 25 3.1 12.5 1.61.6 200 1.6 6.3 100 200 59758 3.1 1.6 50 0.1 200 6.3 12.5 6.3 6.3 2003.1 0.1 200 200 TABLE 1 C ntinucd Compd. a b c d e f h i k l m n o No.MIC (pg/ml) 59857 1.6 1.6 25 0.2 100 25 50 6.3 6.3 200 3.1 25 200 200See Table 2 for structures a S. aurues HH 127 b S. aureus SK 23390 c S.villaluz d= Strep. pyog. C 203 e Strep. faecalis HH 34358 f= E. coli SK12140 g E. coli'HH 33719 h Kleb. pneumo. SK 4200 i= Kleb. pneumo. SK1200 j= Pseudo. sp. HH 63 k Salmonella ATCC 12176 Shigella HR 112 mEmero. aerog. ATCH 13048 n Serra. marc. ATCC 13880 Entero. cloaca PaS L969 TABLE 2 ture with stirring. After 1.25 hours the reaction was ouredinto ice water and the a ueous mixture was Compound No. X A

acidified to pH 2 and extracted with ethyl acetate. The 54293 methylacetoxymethyl 55848 methyl S-methyl-l,3,4 thiadiaz extracts were driedand concentrated to a volume of ylthiomethyi about ml. An equal volumeof ether was added e y I ig y -y followed by sodium 2-ethylhexanoate andthen more m6 57359 phcnyl acetoyxymethyl ether 100 ml.). The precipitatewas collected, washed S7360 phenyl S-methyl-l,3.4-thiadia2ol-2- withether, and dried to yield the title compound as its 59345 l'q l sodiumsalt. The free acid is obtained by acidification methyl py ndlmummethyl59393 ammo acetoxymethyl of an aqueous solution of the sodium salt.59454 methyl methyl 59586 methyl S-methyl-1,2.4-triazol-3- EXAMPLE 2ylthiomethyl 2323? ny: g y r y l 2 7-Methylsulfonylacetam1do-3-(l-methyltetrazol-S- y ylthiomethyl)-3-cephem-4-carboxylic acid 5975smethyl 4-methyl-1,2,4-triazol-3-yl- To a suspension of 7-amino-3-(l-methyltetrazol-S- thiomethyl 59857 methyl 4 methyl s oxo lJAMHOLylthiom ethyl) 3 cephem 4 carboxyllc acid (1.09 g, 3 ylthiomethyl mmol)in dimethylfonnamide (25 ml) was added tri- These compounds areformulated and administered in the same manner as other cephalosporinswith the dose depending on the subject and the infection being EXAMPLE 17-Methylsulfonylacetamidocephalosporanic acid Dicyclohexylcarbodiimide(20.6 g, 0.1 mol) was added to a solution of methylmercaptoacetic acid10.7 g, 0.01 mol) and N-hydroxysuccinimide (l 1.5 g, 0.1 mol) in drytetrahydrofuran (100 ml). The mixture was stirred in an ice bath for onehour and then allowed to stand overnight. The precipitate was collectedand the filtrate was evaporated to give the crude product which wasrecrystallized from carbon tetrachloride.

The above activated ester (4.06 g, 0.02 mol) was dissolved in chloroform(40 ml) and the solution was cooled to 0. To this was added over a 15minute period a solution of m-chloroperbenzoic acid (8.1 g, 0.04 mol) inether (50 ml). The reaction is stirred one hour in an ice bath and threedays at room temperature. The precipitated product was collected and wasrecrystallized from acetoneto give the methylsulfonylacetate ester.

To a suspension of 7-ACA (1.64 g, 0.06 mol) in dry dimethylformamide (20ml) was added sufficient triethylamine to effect solution. The aboveester (1.4 g, 0.06 mol) was added to the solution at room temperaethylamine until all the solid was dissolved. The activatedmethylsulfonylacetate ester from Example 1 (0.705 g, 3 mmol) was addedto the solution in one portion. The reaction solution was stirred atroom temperature for 5 hours and then was added dropwise to ether (200ml). The gummy precipitate was stirred with filter aid and filtered. Thefilter cake was washed with ether, and then stirred with acetonitrile(50 ml) and filtered again. The filtrate was evaporated to a gummyresidue which was dissolved in water (40 ml). The aqueous phase wasextracted with ethyl acetate (40 ml), acidified to pH 2, and reextractedwith ethyl acetate. The organic extracts of the acidic solution werewashed with water, dried and concentrated to a volume of about 50 ml.Sodium 2-ethylhexanoate in isopropanol was added to precipitate thesodium salt of the title compound. The free acid is obtained from thesodium salt by standard methods.

EXAMPLE 3 7-Methylsulfonylacetamido-3-( 2-methyl- 1 ,3 ,4-thiadiazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid Triethylamine wasadded to a suspension of 7-amino- 3-( 2-methyl-1,3,4-thiadiazo1-S-ylthiomethyl )-3-cephem-4-carboxylic acid (1.72 g, 5mmol) in dimethylformamide (25 ml) until a slight cloudiness remained.To this was added the activated sulfonyl ester from Example 1 (1.18 g, 5mmol) and the reaction was stirred at room temperature for 2 hours. Thesolution was poured into ice water ml) and the resultant solution wasextracted with ethyl acetate. The aqueous phase was acidified with 3NHCl to pH 2 and extracted with ethyl acetate. The combined extracts werewashed with water, dried and concentrated to a volume of 50 ml. Sodium2-ethylhexanoate was added and then ether (200 ml). The precipitatedsodium salt was collected, washed with ether and dried. By standardmethods, the free acid is obtained from the sodium salt.

EXAMPLE 4 7-Phenylsulfonylacetamido-3-( 2-methyl- 1 ,3 ,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid Whenphenylmercaptoacetic acid was reacted with N-hydroxysuccinimide and thenm-chloroperbenzoic acid according to the procedure in Example 1, N-hydroxysuccinimidyl phenylsulfonylacetate was obtained.

7-Amino-3-( Z-methyll,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (1.38 g, 0.04mol) was suspendedin dimethylformamide (25 ml) and triethylamine wasadded until solution was effected. The above ester (1.1 g, 0.04 mol) wasadded and the reaction was stirred for 2 hours at room temperature. Thesolution was added dropwise to ether (200 ml). The suspension wasfiltered through filter aid and the filter cake was washed with ether.The product and filter aid were stirred with water (50 ml) for minutesand refiltered. The aqueous filtrate was extracted with ethyl acetate(which was discarded) and then acidified to pH 1 with 3N l-lCl andreextracted with ethyl acetate. The extracts were washed with water,dried, and sodium 2-ethylhexanoate was added. The sodium salt wascollected and dried. An aqueous solution of the sodium salt is adjustedto pH 2 and the free acid is collected.

EXAMPLE 5 7-Phenylsulfonylacetamidocephalosporanic acid When theactivated phenylsulfonylacetate of Example 4 was reacted with 7-ACAaccording to the same procedure as Example 4, the title compound wasobtained.

EXAMPLE 6 7-Trifluoromethylsulfonylacetamido- 3-( 2-methyl- 1 ,3,4-thiadiazol-S-ylthiomethyl )-3-cephern-4-carboxylic acidTn'fluoromethylmethylsulfone (1.48 g, 0.01 mol) [W. E. Truce, et al., J.Amer. Chem. Soc., 74, 3594 (1952)] was dissolved in dry ether (50 ml)and the solution was cooled to 40. A 2 molar solution of n-butyl lithium(7.5 ml, 0.015 mol) was added; the reaction was warmed to ca. 15,stirred for 30 minutes, and then poured over crushed CO with sitrring.When the mixture reached room temperature it was shaken with water (75ml); the aqueous phase was separated, acidified to pH 1.5, and extractedwith ether. The extracts were dried and evaporated to give an oil whichcrystallized on standing. The trifluoromethylsulfonylacetic acid wasrecrystallized from carbon tetrachloride.

Using the procedure in Example 1 trifluoromethylsulfonylacetic acid isesterified with N-hydroxysuccinimide and then is reacted with7-amino-3-(2-methyl- 1 ,3,4-thiadiazol5-ylthiomethyl)-3-cephem-4-carboxylic acid using the procedure of Example 3 to give the titlecompound.

EXAMPLE 7 7-Trifluoromethylsulfonylacetamidocephalosporanic acid Thereaction of the activated ester of trifluoro methylsulfonylacetic acidfrom Example 6 with 7-ACA according to the procedure of Example 1 givesthe title compound.

EXAMPLE 8 tered, washed with ether, then stirred with ethyl acetate andfiltered. The filtrate was treated with sodium 2- ethylhexanoate inisopropanol. The precipitated sodium salt was collected, washed withether and acetonitrile and dried. The sodium salt is converted to thefree acid by standard methods.

EXAMPLE 9 7-Aminosulfonylacetamido-3-( 2-methyl- 1 ,3 ,4-thiadiazol-S-ylthiomethyl)-3cephem-4-carboxylic acid Using the procedureof Example 3, 7-amino-3-(2- methyl-1 3 ,4-thiadiazol-5ylthiomethyl)-3-cephem-4- carboxylic acid is reacted with N-hydroxysuccinimidylaminosulfonylacetate (prepared in a similar manner as set forth inExample 1 from aminosulfonylacetic acid and N-hydroxysuccinimide) togive the desired prod- UCI.

EXAMPLE 10 When an equivalent amount of a 7-amino-3-heterocyclicthiomethyl-3-ccphem-4-carboxylic acid listed below issubstituted in Example 2 for 7-amino-3- 1methyltetrazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid, the appropriate 7-methylsu1-fonylacetamido-3heterocyclicthiomethyl-3-ccphem-4- carboxylic acid isobtained.

7-Amino-3-( 1 ,3,4-thiadiazol-2-ylthiomethyl)-3- cephem-4-carboxylicacid 7-Amino-3-( S-trifluoromethyl- 1 ,3 ,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amin o-3-( S-ethyl-l ,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amin o-3-( 5n-butyl- 1 ,3 ,4-thiadiazol-2-ylthiome thyl)-3-cephem-4-carboxylic acid7-Amino-B-(S-dimethylamino-l ,3,4-thiadiazol-2-ylthiomethyl)-3-ccphem-4-carboxylic acid 7-Amin o-3-( 5-mercapto-1 ,3,4-thiadiazol-3-ylthiomethyl)cephem-4-carboxylic acid7-Amino-3-(3-methylthio-1,2,4-thiadiazol-5-ylthiomethyl)3-cephem-4-carboxylic acid 7-Amino-3-(3-methyl-1 ,2,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid7Amin o-3-(tetrazol-5ylthiomethyl )-3-cephem-4- carboxylic acid7-Amino-3-( l ,2,4-triazol-3-ylthiomethyl)-3-cephem- 4-carboxylic acid7-Amino-3-( S-methyll ,2,4-triazol-3-ylthiomethyl 3-cephem-4-carboxylicacid 7-Amino-3-(4-methyll ,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(4,5-dimethyll,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(2,5-dimethyl-l ,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid7-Amino-3 -(4-methyl-5-trifluoromethyll ,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-( S-ethyl-l,2,4-triazol-3-ylthiomethyl )-3- cephem-4-carboxylic acid7-Amino-3-(4-ethyl-l ,2,4-triazol-3-ylthiomethyl )-3-cephem-4-carboxylic acid 7-Amino-3 2-methyl-l 2,4-triazol-3-ylthiomethyl3-cephem-4-carboxylic acid 7-Amino-3-( 2-ethyll,2,4-triazol-3-ylthiomethyl )-3- cephem-4-carboxylic acid7-Amino-3-(4-allyll ,2,4-triazol-3-ylthiomethyl )-3- cephem-4-carboxylicacid 7-Amino-3 S-methoxym ethyll,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-35-cycloprop yll ,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid7-Amino-3-( 5-bromo- 1 ,2 ,4-triazol-3-ylthiomethyl3-cephem-4-carboxylic acid 7-Amino-3-( S-hydroxy-l,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(5-hydroxy-4-methyll ,2,4-triazol-3- ylthiomethyl )-3-cephem-4-carboxylicacid 7-Amino-3 5-hydroxy-4-ethyl-l,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid 7-Amino-3-(l,2,3-triazol-5-ylthiomethyl)-3-cephem- 4-carboxylic acid 7-Amino-3-(l,3,4-oxadiazol-2-ylthiomethyl)-3-ccphem-4-carboxylic acid 7-Amino-3-(5-methyl-1 3 ,4-oxadiazol- 2-ylthiomethyl)-3-cephem-4-carboxylic acid7-Amino-3-(4pyrimidylthiomethyl)-3-cephem-4- carboxylic acid 7-Amino-3-(2-pyrazinylthiomethyl )-3-cephem-4- carboxylic acid 7-Amino-3-(3-pyridylthiomethyl)-3-cephem-4-carboxylic acid I7-Amino-3-(4-pyridylthiomethyl)-3-cephem-4-carboxylic acid EXAMPLE 1 lThe reaction of 7-amino-3-(l-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid or a7-amino-3- heterocyclicthiomethyl-3-cephem-4-carboxylic acid enumeratedin Example 10 with activated phenylsulfonylacetate ester according tothe procedure of Example 4 -carboxylic the appropriate7-phenylsulfonylacetamido-3-heterocyclicthiomethyl-3-cephem-4-carboxylic acid.

EXAMPLE 12 When the procedure of Example 6 is followed using 7-amino-3-(l-methyltetrazol-S -ylthiomethyl )-3-cephem-4-carboxylic acid or a7-amino-3-heterocyclicthiomethylcephalosporin listed in Example 10, thecorresponding 7-trifluoromethylsulfonylacetamido-3-heterocyclicthiomethyl-3-cephem-4-carboxylic acid is obtained.

EXAMPLE l3 Substitution of7-amino-3-(l-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acidor a cephalosporin compound listed in Example 10 in the procedure ofExample 9 gives the appropriate7-aminosulfonylacetamido-3-heterocyclicthiomethyl-3-cephem-4- carboxylicacid product.

EXAMPLE l4 7-Methylsulfonylacetamido-3-( l-pyridiniummethyl )-3-cephem-4-carboxylic acid To a solution of7-methylsulfonylacetamidocephalosporanic acid sodium salt 1.75 g, 4.0mmol) in water (2 ml) was added potassium thiocyanate (7.87 g, 0.081mol), water (2 ml) and pyridine (0.44 ml). The reaction was heated at6570 for 7 hours and then was cooled. The solution was diluted withwater ml) and the aqueous solution was chromatographed on a column ofcross-linked polystyrene polymer (125 g of Amberlite XAD-2). Theinorganic salts were eluted with water and then the product was elutedwith ethanol. The ethanol fractions were evaporated to give the crudeproduct which was dissolved in water, filtered and lyophilized.

EXAMPLE 15 When trifluoromethylsulfonylacetamidocephalosporanic acid,aminosulfonylacetamidocephalosporanic acid, orphenylsulfonylacetamidocephalosporanic acid is substituted formethylsulfonylacetamidocephalosporanic acid in Example 14 thecorresponding 3-(1- pyridiniummethyl)cephalosporin is obtained.

EXAMPLE l6 7-(N,N-Dimethylaminosulfonylacetamido)-3-(2-methyll,3,4-thiadiazol-5-yl )-3-cephem-4-carboxylic acidN,N-Dimethylaminosulfonylacetic acid is prepared in an analogous methodas aminosulfonylacetic acid and then is reacted with7-amino-3-(2-methyl-l,3,4-thiadiazol-S-ylthiomethyl)-3-cephem-4-carboxylic acid according to theprocedure of Example 9 to give the title compound.

EXAMPLE 17 When 7-amino-3-( l-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid or a 7-amino-3-heterocyclic cephalosporinenumerated in Example 10 is reacted with N,N-dimethylaminosulfonylaceticacid by the procedure of Example 16 the corresponding 7-(N,N-dimethylaminosulfonylacetamido)-3-heterocyclicthiomethyl-3-cephem-4-carboxylicacid is obtained.

EXAMPLE 18 The reaction of N,N-dimethylaminosulfonylacetic acid with7-ACA t-butyl ester according to the procedure of Example 8 gives7-(N,N-dimethylaminosulfonylacetamido) cephalosporanic acid.

When the above product is reacted with pyridine using the procedure ofExample 14, 7-(N,N-dimethylsulfonylacetamido)-3-(l-pyridiniummethyl)3-cephem-4-carboxylic acid is obtained.

EXAMPLE l9 7:Methylsulfonylacetamido-3-methyl-3-cephem-4-carboxylic acid7-Amino-3-methyl-3-cephem-4-carboxylic acid (7- ADCA) (2.14 g, 0.01 mol)was suspended in dry dimethylformamide (30 ml) and1,5-diazobicyclo[4.3.0]non--ene was added until only a slight cloudinessremained. The activated ester from Example 1 (2.35 g, 0.01 mol) wasadded and the reaction was stirred for 2.5 hours at room temperature.The solution'was filtered into ether (300 ml) and then the filtrate wasfiltered through filter aid. The filter cake was stirred with water (50ml) and refiltered. The filtrate was acidified to pH 1.5 with 3N HC] andextracted with ethyl acetate. The organic extracts were washed withwater, dried, and concentrated to ca. 50 ml. Sodium 2-ethylhexanoate wasadded and the precipitated sodium salt was collected, washed with ethylacetate and dried. The free acid is obtained from the sodium salt bystandard methods.

- EXAMPLE 20 When the activated esters of phenylsulfonylacetic acid,trifluoromethylsulfonylacetic acid, aminosulfonylacetic acid, orN,N-dimethylaminosulfonylacetic acid are reacted with 7-ADCA accordingto the procedure in Example 19 the corresponding7-sulfonylacetamido-3-methyl-3-cephem-4-carboxylic acid is obtained.

EXAMPLE 21 7-Ethylsulfonylacetamidocephalosporanic acidN-hydroxysuccinimidyl ethylsulfonylacetate was prepared fromethylmercaptoacetic acid according to the procedure of Example 1. To asuspension of 7-ACA (2.18 g, 8 mmol) in dry dimethylformamide (50 ml)was added triethylamine until solution was effected and then theactivated ester (1.99 g, 8 mmol) was added in one portion. The resultantreaction mixture was stirred 1.5 hours at room temperature and thenpoured with stirring into ether (400 ml) which caused a gummy residue toprecipitate. The mixture was filtered through Celite and the filter cakewas stirred with water (100 ml) until the residue was dissolved. Theaqueous solution was filtered, washed with ethyl acetate, covered withfresh ethyl acetate and acidified with 3N HCl to pH 2. The acidicsolution was extracted wtih ethyl acetate. The combined extracts werewashed with water, dried, and evaporated to give the title compound.

EXAMPLE 22 7-Ethylsulfonylacetamido-3-(2-methyl-l ,3,5-thiadiazol-S-ylthiomethyl)-3-cephem 4-carboxylic acid Using theactivated 7.-ethylsulfonylacetate ester (1.99 g, 8 mmol) and7-amino-3-(2-methyl-l,3,5-thiadiazOl-S-ylthiomethyl)-3-cephem-4-carboxylic acid (2.75 g, 8 mmol)in the procedure of Example 21, the title compound was prepared.

EXAMPLE 23 When 7-amino-3-( l-methyltetrazol-5-ylthiomethyl)-3cephem-4-carboxylic acid or any of the compounds enumerated in Example10 are substituted for 7-ACA in the procedure of Example 21 thecorresponding 7-ethylsulfonylacetamido-3-heterocyclicthiomethyl-3-cephem-4-carboxylic acid is obtained.

Similarly, 7-ethy1sulfonylacetamido-3-methyl-3- cephem-4-carboxylic acidis obtained by acylating 7- ADCA using the procedure of Example 21.

EXAMPLE 24 Propylmercaptoacetic acid is converted into N-hydroxysuccinimidyl propylsulfonylacetate in the same manner as themethyl analog in Example 1. This ester is reacted with 7-ACA, 7-ADCA,7-amino-3-(2-methyl- 1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, 7-amino-3-(l-methyltetrazol- 5-ylthiomethyl)- 3-cephem-4-carboxylic acid, or any ofthe compounds enumerated in Example 10 according to the procedure ofExample 21 to give the appropriate7-propylsulfonylacetamidocephalosporin.

EXAMPLE 25 Acylation of 7-amino-3-methylthiomethyl-3-cephem-4-carboxylicacid (Belgian Pat. No. 743,754) with the activated esters ofmethylsulfonylacetic acid, ethylsulfonylacetic acid, orpropylsulfonylacetic acid according to the procedure of Example 1 givesthe corresponding7-alkylsulfonylacetamido-3-methylthiomethyl-3-cephem-4-carboxylic acid.Using the procedure of Example 8 the above cephem nucleus is acylatedwith 'dimethylaminosulfonylacetic acid to give7-dimethylaminosulfonylacetamido-3-methylthiomethyl-3-cephem-4-carboxylic acid.

EXAMPLE 26 EXAMPLE 273-Formyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid7-(2-Thienylacetamido)cephalosporanic acid (45 g, 0.11 mol) wasdissolved in dry pyridine ml) by warming. This solution was cooled in anice bath and acetic anhydride (13.5 ml) was added with stirring. Afterstirring 0.5 hour the reaction was stored in a refrigerator 18 hoursduring which time the mixture was solidified. Ether was added to themixture andthe solid pyridine salt was collected and washed with ether.The salt was suspended in ethyl acetate (400- ml) with stirring and wascollected again. The salt was then dissolved in a mixture of water (300ml), ethyl acetate (400 ml) and 2N HCl (54 ml); the aqueous phase wassaturated with NaCl and then was separated. The organic phase was washedwith saturated NaCl solution, filtered through coarse filter paper threetimes, and evaporated to yield the A -isomer- (32.4 g).

The A -isomer (32.4 g) was suspended in a mixture of acetone (60 ml) andwater (300 ml) and 5% Na CO solution was added until pH 10.5 wasreached. The solution was allowed to stand two days during which timeadditional 5% Na CO was added several times to maintain the solution atpH 10.5. The reaction was cooled in ice, layered with ethyl acetate andacidified 1 1 with 6N H SO pH 1.8. The aqueous phase was saturated withNaCl and separated. The organic phase was washed with saturated NaClsolution, filtered through coarse filter paper and evaporated to givethe product,

the A -3-hydroxymethyl compound (17.4 g). p

- A solution of the above product (17.4 g, 0.049 mol) in acetone (850ml) was cooled to l and then Jones reagent [chromic trioxide (26.72 g)dissolved in concentrated H 50 (23 ml) and then diluted to 100 ml withwater] was added dropwise until the brown color persisted. Excess Jonesreagent was decomposed with isopropanol, the green reaction mixture wasfiltered and the green precipitate was washed with acetone. The combinedfiltrate and washings were diluted with water (200 ml) and ethyl acetate(400 ml) and then saturated with NaCl. The organic phase was-separated,washed with saturated NaCl solution and dried over MgSO Evaporation ofthe solvent gave the crude product which was triturated with methanol togive the product as its methanoate (8.4 g). This product was dissolvedin ethyl acetate (2000 ml) and then evaporated in vacuo to give thetitle compound (7.8 g).

EXAMPLE 28 Benzhydryl 3-formyl-7-(2-thienylacetamido)-2-cephem-4-carboxylate A solution ofdiphenyldiazomethane (0.213 g, 1.1 mmol) in dry tetrahydrofuran (2 ml)was added dropwise with stirring to the 3-formyl-7-(2-thienylacetamido)-2-cephem-4-carboxylic acid (0.352 g., 1 mmol) in drytetrahydrofuran ml) at 40. The reagent was allowed to completely reactas noted by the color changes between each addition. The reaction wasstirred at 40 for 2 hours after the addition was completed and then thesolvent was removed in vacuo. The residual 'oil' was dissolved inchloroform, washed with 5% Nal-ICO dried over MgSO and concentrated tohalf volume. The product was precipitated by the addition of hexane.

EXAMPLE 29 Benzhydryl-7-( 2-thienylacetamido)-3-cephem-4-carboxylate Amixture of the benzhydryl ester from Example 28 (2.5 g, 4.79 mmol),tris-(triphenylphosphine)chlororhodium (3.5 g, 4.79 mmol) and drytoluene (75 ml) was refluxed under nitrogen for 5.5 hours. The reactionmixture was cooled, the rhodium complex was removed by filtration andthe filtrate was poured slowly into petroleum ether (250 ml) withstirring. The precipitated solid, which was a mixture of rhodium complexand product, was collected. The product was purified by chromatographyon a silica gel column (250 g) using 99:0.5 chloroformtethyl acetate aseluent. Fractions of 4.5 ml were collected; fractions l-47 discarded48-66 contained bis-(triphenylpho'sphine)carbonylchlororhodium, and67-198 contained the product. NMR data indicated the product afterchromatography to be the A isomer instead of the A isomer. A decouplingexperiment showed the 2-methylene group at 3.3

ppm. to be coupled with the 3-proton at 6.6 ppm.

EXAMPLE 30 at 0 and PCl (1.54 g, 7.4 mmol.) was added with stirring. Thereaction mixturewas stirred under nitrogen at 0 for three hours and thenthe solvent was removed in vacuo. Anhydrous methanol (260 ml) was addedto the residue and the resultant. mixture was allowed to stand twohours. The methanolwas removed in vacuo and the residue was treated wtih20% aqueous tetrahydrofuran. After 15 minutes the tetrahydrofuran wasremoved in vacuo and the aqueous residue was adjusted to pH 7.5 andextracted with ethyl'acetate. The extracts were washed with water, driedover MgSO and evaporated to give the solid product which was trituratedwith chloroform-petroleum ether and dried under high vacuum.

EXAMPLE 3 1 7-Methylsulfonylacetamido-3-cephem-4-carboxylic acid Asolution of benzhydryl 7-amino-3-cephem-4-carboxylate (0.78 g, 2 mmol),methylsulfonylacetic acid (0.27 g, 2 mmol), and dicyclohexylcarbodiimide(0.4 g, 2 mmol) in dry tetrahydrofuran (15 ml) is stirred at roomtemperature overnight. The precipitate is collected and washed withtetrahydrofuran and the combined filtrate and washings are evaporated invacuo. The residue is treated with a cold solution of trifluoroaceticacid (10 ml) and anisole (0.5 g) for 15 minutes and then concentrated invacuo The residue is dissolved in ethyl acetate and treated with 5%NaHCO The aqueous phase is adjusted to pH 2 and the precipitated productis collected and dried.

EXAMPLE 32 EXAMPLE 33 An injectable pharmaceutical composition is formedby adding sterile water or sterile saline solution (2 ml) to 500 mg ofsodium 7-methylsulfonylac'etamido-3lmethyltetrazol-S-ylthiomethyl)-3-cephem-4-carboxylate.

Pharmaceutical compositions of the other antibacterial compoundsdisclosed above may be formulated in a .similar manner.

i A t X-SO CH CONH I pound 7-aminosulfonylacetamido-3-(l-pyridiniummethyl)-3-cephem-4-carboxylic acid.

5. A compound as claimed in claim 2 being the compound7-(N,N-dimethylaminosulfonylacetamido)cephalosporanic acid. 7

6. A compound as claimed in claim 2 being the compound7-aminosulfonylacetamido-3-methyl-3-cephem- 4-carboxylic acid.

7. A compound as claimed in claim 2 being the compound7-aminosulfonylacetamido-3-cephem-4-carboxylic acid.

8. A compound as claimed in claim 2 being the compound7-(N,N-dimethylaminosulfonylacetamido)-3- cephem-4-carboxylic acid.

1. A COMPOUND OF THE STRUCTURE:
 2. A compound as claimed in claim 1where X is NH2 or N(CH3)2.
 3. A compound as claimed in claim 2 being thecompound 7-aminosulfonylacetamidocephalosporanic acid.
 4. A compound asclaimed in claim 2 being the compound7-aminosulfonylacetamido-3-(1-pyridiniummethyl)-3-cephem-4-carboxylicacid.
 5. A compound as claimed in claim 2 being the compound7-(N,N-dimethylaminosulfonylacetamido)cephalosporanic acid.
 6. Acompound as claimed in claim 2 being the compound7-aminosulfonylacetamido-3-methyl-3-cephem-4-carboxylic acid.
 7. Acompound as claimed in claim 2 being the compound7-aminosulfonylacetamido-3-cephem-4-carboxylic acid.
 8. A compound asclaimed in claim 2 being the compound7-(N,N-dimethylaminosulfonylacetamido)-3-cephem-4-carboxylic acid.